XBP1 is a critical determinant of several outcomes following activation of the unfolded protein response (UPR). This UPR gene is initially transcribed as an unspliced mRNA but can subsequently be spliced by the endoribonuclease activity of IRE1α induced by activation of GRP78 in response to endoplasmic reticulum stress. Both the unspliced (XBP1-U) and spliced (XBP1-S) mRNAs are translated into proteins. XBP1-U, which cannot function as a transcription factor, can act as a dominant negative regulator of XBP1-S. In contrast, the frameshift produced by the removal of 26 bp intron from an already matured XBP1 mRNA, produces a transcription factor (XBP1-S). This chapter discusses the regulation and unconventional splicing of XBP1 and the roles of both the unspliced and spliced proteins in breast cancer, with a focus on those breast cancers expressing the estrogen receptor.